tbuckley/cabot-search huggingface dataset:
Abstract 4003: Identification of a targeted anti-mitotic agent that degrades Myc and specifically induces cancer cell death
Authors: Jessica McAnulty, Michele Dziubinski, Agharnan Gandhi, Margaret Farah, Pil Lee, Andrew D. White, Analisa DiFeo
Journal: Cancer Research (2022)

Abstract For decades, chemotherapy has remained the standard of care for ovarian cancer patients. Although 70% of patients initially respond to platinum-based therapy, &amp;gt;90% succumb to chemoresistance. There is a need to uncover targeted drugs for ovarian cancer. A quicker, more cost-effective, and lower-risk route to identify new treatments is through repurposing FDA approved drugs. Using a computational drug repositioning platform, DrugPredict, we previously uncovered that the antiarrhythmic drug amiodarone potently decreases cell viability and triggers apoptosis in numerous patient-derived ovarian cancer cell lines through the degradation of c-Myc. However, given the dose-limiting toxicity of amiodarone, we applied structure-activity relationship to identify DL78, which lacks hERG activity but retains the anti-cancer properties and ability to regulate Myc. DL78 is significantly more potent and tumor specific than amiodarone. It rapidly induces G2/M arrest which ultimately leads to loss of Myc, mitotic catastrophe, and apoptosis in several types of cancer cells. Furthermore, pharmacokinetics studies show that the compound is retained in the tumor upon intraperitoneal injection and has reasonable solubility and permeability, yielding good absorption, distinct from amiodarone. Given its structural and molecular differences, we expect that DL78 works through a different mechanism that amiodarone and could represent an effective treatment for ovarian cancer and other MYC-driven tumors. Additional studies will establish the foundation for further development of this novel compound, as well as reveal targeted ovarian cancer vulnerabilities. Citation Format: Jessica McAnulty, Michele Dziubinski, Agharnan Gandhi, Margaret Farah, Pil Lee, Andrew D. White, Analisa DiFeo. Identification of a targeted anti-mitotic agent that degrades Myc and specifically induces cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4003.
Aberrant <i>EVI1</i> splicing contributes to <i>EVI1</i>-rearranged leukemia
Authors: Atsushi Tanaka, Taizo A. Nakano, Masaki Nomura, Hiromi Yamazaki, Jan P. Bewersdorf, Roger Mulet-Lazaro, Simon Hogg, Bo Liu, Alex Penson, Akihiko Yokoyama, Weijia Zang, Marije Havermans, Miho Koizumi, Yasutaka Hayashi, Hana Cho, Akinori Kanai, Stanley C. Lee, Muran Xiao, Yui Koike, Yifan Zhang, Miki Fukumoto, Yumi Aoyama, Tsuyoshi Konuma, Hiroyoshi Kunimoto, Toshiya Inaba, Hideaki Nakajima, Hiroaki Honda, Hiroshi Kawamoto, Ruud Delwel, Omar Abdel-Wahab, Daichi Inoue
Journal: Blood (2022)

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).
Abstract 257: Normalization of tumor stroma improves the anti-tumor activity of anti-PD-L1 peptides in pancreatic cancer
Authors: Chien-Yu Lin, Kun Cheng
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by the abundant fibrotic stroma surrounding malignant epithelial cells. The tumor stroma is composed of extracellular matrix proteins, myofibroblasts, stellate cells, and immune cells, and comprises up to 80% of the tumor mass. The stroma promotes the progression and metastasis of tumors and the development of chemoresistance. However, the strategies of completed depletion of the stroma resulted in a more aggressive tumor and a poor survival rate in clinical trials. We discovered that silencing the RNA binding protein αCP2, which is encoded by the poly(rC)-binding protein 2 (PCBP2) gene, could destabilize the type I collagen mRNA in human pancreatic stellate cells and mouse NIH/3T3 fibroblasts, leading to the normalization of the tumor stroma. We recently discovered an anti-PD-L1 peptide that effectively blocks the PD1/PD-L1 pathway. We hypothesize that silencing αCP2 modulates the PDAC stroma, thus improving the therapeutic efficacy of immunotherapy. Therefore, the objective of this study is to develop a combination therapy strategy to treat PDAC with PCBP2 siRNA nanoparticles and the anti-PD-L1 peptide. A mixture of 1×106 PANC02 tumor cells and NIH/313 fibroblast cells was subcutaneously implanted into C57BL/6 mice to establish the desmoplastic PDAC model. The mice were treated with saline, PCBP2 siRNA nanoparticles, the anti-PD-L1 peptide, and PCBP2 siRNA nanoparticles plus the anti-PD-L1 peptide. The results showed that the combination of PCBP2 siRNA nanoparticles with the anti-PD-L1 peptide reduced tumor growth. PCBP2 siRNA decreased type I collagen expression in the tumor. The normalized stroma showed increased infiltration of effective immune cells. This approach provides a new strategy to improve the therapeutic efficacy of immunotherapy in PDAC by normalizing the tumor stroma with the PCBP2 siRNA nanoparticle. Citation Format: Chien-Yu Lin, Kun Cheng. Normalization of tumor stroma improves the anti-tumor activity of anti-PD-L1 peptides in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 257.
Abstract CT256: A pilot clinical study of VAL-413 (Orotecan®, oral irinotecan HCl) in patients with recurrent pediatric solid tumors
Authors: James Geller, Patrick Thompson, Javier Oesterheld, Dennis M. Brown, Jeffrey Bacha, Sarath Kanekal, Lorena Lopez, Markos Leggas, Neil Sankar, Noymi Yam, Lars M. Wagner
Journal: Cancer Research (2022)

Abstract Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to improve convenience, reduce in-clinic time and overall cost of treatment. Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. We will report on an ongoing Phase 1-2 first-in-human clinical trial of VAL-413, designed to test the hypothesis that VAL-413 improves palatability without significant pharmacokinetic differences from IRN-IVPO using intra-patient comparison of pharmacokinetic profiles. The evaluation of two dose levels will help to formally define a recommended dose for advanced clinical studies. Trial Design: Patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option, are eligible. Up to 20 eligible patients will receive VAL-413 90mg/m2/day or 110mg/m2/day using a standard 3 + 3 design. During the first cycle of treatment, each patient will receive four daily doses of VAL-413 and one daily dose of IRN-IVPO, together with five (5) days of concurrent temozolomide. Pharmacokinetic assessments will follow both VAL-413 and IRN-IVPO administration using a limited sampling strategy. During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days. Up to 17 cycles of treatment may be administered on this study. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; and comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed in all patients. Citation Format: James Geller, Patrick Thompson, Javier Oesterheld, Dennis M. Brown, Jeffrey Bacha, Sarath Kanekal, Lorena Lopez, Markos Leggas, Neil Sankar, Noymi Yam, Lars M. Wagner. A pilot clinical study of VAL-413 (Orotecan®, oral irinotecan HCl) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT256.
Abstract 3982: Molecular mechanism of cisplatin-induced p53 activation, cell cycle regulation, and apoptosis in acute leukemia cells
Authors: Paul B. Tchounwou, Sanjay Kumar
Journal: Cancer Research (2022)

Abstract Cisplatin (CDDP) is an anticancer drug successfully used in the treatment of various human malignancies. Although it has been shown to enhance the potency of arsenic trioxide in chronic myelogenous leukemia (CML) cells and to induce cytotoxicity in acute promyelocytic leukemia (APL) cell lines, its molecular mechanism of action is mostly unknown. We investigated a novel mode of action of CDDP through modulation of stress signals, disruption of MDM2-DAXX-HAUSP complex, and activation of p53 in APL cell lines. We found that CDDP-induced stress signals were transmitted and reduced expression of complex molecules and also effected their association leading to p53 activation. CDDP-activated p53 led to cell cycle arrest and induced both early and late apoptosis in APL cells. Our findings also showed that CDDP stimulated more promyelocytes formation with dense granules, activated p53 expression, and reduced expression of MDM2 in both APL mice bone marrow cells and liver tissues. This novel mechanism of action of CDDP in APL cells may help in the design of new anti-leukemic drugs for treatment of APL patients. Citation Format: Paul B. Tchounwou, Sanjay Kumar. Molecular mechanism of cisplatin-induced p53 activation, cell cycle regulation, and apoptosis in acute leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3982.
Abstract 4123: Real-world data to identify the genomic association with response to CDK4/6i + Endocrine therapy in ER+ breast cancer patients
Authors: Kun Yu, Tenghui Chen, Manav Korpal, Ping Zhu, Zhaojie Zhang, Lihua Yu, Yonghong Xiao
Journal: Cancer Research (2022)

Abstract Background Real-world data (RWD) has been increasingly used for drug development. RWD coupled with genomic data provides an opportunity to identify the association between certain genomic alterations and response to current standard of care (SOC). Such analyses may help identify predictive biomarkers to select patients who will benefit most from SOC, and/or potential therapeutic nodes that can be pharmacologically targeted to overcome resistance to SOC. Methods We obtained Flatiron CGDB Breast Cancer (as of Q3 2020 release) data set. This data set includes clinical and genomic data from 6,918 breast cancer patients. Time to treatment discontinuation (TTD) was used as real world outcome. We performed two types of genomic-outcome association analysis: 1) Use Cox proportional hazards regression model to identify which baseline mutation (mutation occurred prior to the treatment) could predict the outcome; and 2) use Fisher exact test to identify which mutations are enriched in post-treatment tumors samples, compared to pre-treatment tumor samples. Result We found TP53 mutation is associated with shorter TTD for Palbociclib + Aromatase inhibitor (AI); Palbociclib + Fulvestrant; and endocrine monotherapy. It is consistent with the reports that TP53 mutation is poor prognostic factor (ref). Interestingly, ESR1 mutation is associated with shorter TTD for Palbociclib + AI and AI monotherapy; but not associated with TTD for Palbociclib + Fulvestrant or Fulvestrant monotherapy. On the other hand, MYC amplification is associated shorter TTD for Palbociclib + Fulvestrant or Fulvestrant monotherapy. We found that genes associated with Palbociclib + Endocrine are by and large same as those associated with endocrine monotherapy; suggesting the association is largely driven by endocrine treatment. Comparison of post-treatment vs. pre-treatment analysis found that ESR1 mutation is enriched in post treatment of AI; but not Fulvestrant. Conclusion We demonstrated that real-world clinicogenomic data could identify the biologically meaningful genomic biomarkers that are associated with real world response. This study warrants the further investigation of novel genomic biomarkers identified from the analysis. Citation Format: Kun Yu, Tenghui Chen, Manav Korpal, Ping Zhu, Zhaojie Zhang, Lihua Yu, Yonghong Xiao. Real-world data to identify the genomic association with response to CDK4/6i + Endocrine therapy in ER+ breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4123.
Abstract 3892: High-throughput combination screen for identifying novel therapies against high-risk neuroblastoma
Authors: Katarzyna Radke, Karin Hansson, Jani Saarela, Aleksandr Ianevski, Philipp Ianevski, Aurélie Baudet, Mattias Magnusson, Daniel Bexell
Journal: Cancer Research (2022)

Abstract Neuroblastoma is a childhood solid tumor commonly located in the adrenal gland. High-risk neuroblastoma patients undergo multidrug and multi-interventional treatment but despite these efforts many patients develop resistance to chemotherapy and eventually relapse. Neuroblastoma patients face an urgent need of novel therapeutic strategies that could effectively combat the disease. In a recent study we identified kinesin spindle protein (KSP) as a highly effective target in high-risk neuroblastoma. Pharmacological inhibition of KSP resulted in complete regression of a subset of neuroblastoma subcutaneous PDX tumors and tumor growth delay in orthotopic PDXs (Hansson, Radke et al, Sci. Transl. Med 2020). The purpose of the present study is to identify novel synergistic drug combinations effective against neuroblastoma and investigate their translational potential. We designed, optimized, and performed a high-throughput combination screen using 3D tumor organoids that represent three MYCN-amplified neuroblastoma tumors. KSP inhibition was tested in combination with the FIMM drug set of 527 approved and investigational drugs. Screening was performed stepwise: • Step 1: High-throughput drug screening 527 drug combinations and machine learning prediction (DECREASE tool) of drug combination synergy based on minimal required input. • Step 2: Screening of 6x6 dose-response matrices of top 26 predicted hits in high-risk neuroblastoma models. • Step 3: Screening of 6x6 dose-response matrices of top 26 hits in CD34+ cord blood controls to identify compounds that have low toxicity towards proliferating fraction of hematopoietic cells. Overall, we identified seven drug candidates (P1-P7). They classify as: kinase inhibitors, differentiating modifiers, and one hormone therapy. Screened combinations were chosen based on selective efficacy (difference between anti-neuroblastoma efficacy and efficacy towards CD34+ cord blood controls). Identified drug combinations are common among three high-risk neuroblastoma models and have most synergistic area score (MSA) over five. We further plan to validate seven hits in neuroblastoma models in vitro, investigate MOA of the most promising combination and test it in PDX models in vivo. Citation Format: Katarzyna Radke, Karin Hansson, Jani Saarela, Aleksandr Ianevski, Philipp Ianevski, Aurélie Baudet, Mattias Magnusson, Daniel Bexell. High-throughput combination screen for identifying novel therapies against high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3892.
Abstract 2687: The estrogenic activities of endocrine disruptors alter the extracellular matrix and tissue stiffness in the mammary gland
Authors: Clarissa Wormsbaecher, Andrea R. Hindman, Alex Avendano, Marcos Cortes-Medina, Jonathan W. Song, Craig J. Burd
Journal: Cancer Research (2022)

Abstract In utero exposure to estrogenic endocrine disrupting compounds (EDCs) increases a woman’s lifetime risk of breast cancer. Similarly, mice exposed in utero to the estrogenic EDC bisphenol A (BPA) have increased susceptibility to mammary gland tumors. It is unclear which BPA-induced alterations predispose the mammary gland to cancer transformation. There is a critical need to understand the mechanisms that drive increased cancer risk in order to assess the impact of BPA and BPA alternatives that retain estrogenic activity. We have utilized in utero BPA exposure as a model system for in utero estrogenic endocrine disruption to study the long-term consequences to the mouse mammary stroma. We found that BPA exposed fibroblasts showed significant transcriptional deregulation, with the extracellular matrix being the most altered cellular component and multiple collagen genes being more highly expressed. The fibroblasts from the BPA exposed mice decreased fluid permeability of the extracellular matrix, indicative of an increased density in the extracellular matrix. Also, in utero BPA exposure increased mammary gland stiffness. Changes to breast density, stiffness, and collagen deposition are all associated with breast cancer risk. Further, we test BPA alternative compounds with varying affinities for the estrogen receptor in our in utero model to assess the phenotypes in the mouse mammary stroma which are associated with breast cancer risk. Additionally, we use a mesenchymal estrogen receptor alpha (ERα) knockout mouse model to dissect the in utero cellular target of EDCs. Citation Format: Clarissa Wormsbaecher, Andrea R. Hindman, Alex Avendano, Marcos Cortes-Medina, Jonathan W. Song, Craig J. Burd. The estrogenic activities of endocrine disruptors alter the extracellular matrix and tissue stiffness in the mammary gland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2687.
Abstract PL04-03: Germline and microbiome variants impact immunotherapy efficacy through modulation of myeloid cells
Authors: Thomas F. Gajewski
Journal: Cancer Research (2022)

Abstract Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically relevant and grow nonetheless implies that immune escape must occur to allow cancer outgrowth. We have observed two major phenotypes of human melanoma metastases based on gene expression profiling and confirmatory assays. One subgroup of patients has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and appears to display immune “exclusion”. Factors that influence the degree of spontaneous immune infiltration are being investigated, as sources of inter-patient heterogeneity. These include tumor cell-intrinsic oncogenic events, the composition of the gut microbiota, and polymorphisms in immune regulatory genes. We now know that each of these dimensions can be functionally important. The first tumor cell-intrinsic oncogenic pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway. Tumors with active β-catenin fail to recruit Batf3-lineage dendritic cells into the tumor site. Regarding the commensal microbiota, mouse models identified commensal Bifidobacterium as one key component that augments spontaneous anti-tumor immunity and increases efficacy of anti-PD-L1 therapy in vivo. Similar analyses in human cancer patients revealed bacteria sequences enriched in anti-PD-1 responders, and also bacteria sequences enriched in non-responders. Fecal transfer into germ-free mice has confirmed a causal role for the gut microbiota in regulating immunotherapy efficacy. Recent experiments have revealed that one major mechanism by which gut microbes impact on distant ani-tumor immunity is through modulation of immune-regulatory myeloid cells, ie the M1/M2 ratio and MDSCs. Regarding germline variants, our first identified SNP connected to immune cell infiltration is in the PKCδ gene. Loss of function variants are associated with greater immune cell infiltration. PKCδ knockout hosts show improved immune-mediated tumor control and anti-PD-L1 efficacy, but with comparable T cell priming. However, activated T cell accumulation in the tumor microenvironment increases overtime, which is associated with a shift from M2 to M1. Myeloid cell-specific PKCδKO mice using LysM-Cre Tg mice recapitulate the phenotype. Thus, in each of these 3 instances, tumor and host factors impact on anti-tumor immunity by modulating myeloid cell participation—Batf3-DCs, MDSCs, and M1/M2 cells. Citation Format: Thomas F. Gajewski. Germline and microbiome variants impact immunotherapy efficacy through modulation of myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr PL04-03.